Aryl piperidine derivatives and use thereof to reduce elevated levels of ldl-cholesterol

ABSTRACT

This invention relates to novel compounds which up-regulate LDL receptor (LDL-r) expression and to processes for their preparation, pharmaceutical compositions containing them and their medical use. More particularly, this invention relates to novel aromatic piperidines and their use in therapy.

This invention relates to novel compounds which up-regulate LDL receptor(LDL-r) expression and to processes for their preparation,pharmaceutical compositions containing them and their medical use. Moreparticularly, this invention relates to novel aromatic piperidines andtheir use in therapy.

Epidemiological studies have clearly demonstrated the correlationbetween reduction in plasmatic LDL cholesterol and the benefit oncardiovascular events including mortality. LDL cholesterol is eliminatedfrom plasma by specific binding to LDL-r expressed by the liver.Regulation of LDL-r expression occurs in the liver and is mainlydependent on intracellular cholesterol concentration. Increasing freecholesterol concentration leads to a reduced LDL-r expression through amechanism involving transcriptional factors. Counteracting with thisprocess is expected to up-regulate LDL-r expression in the liver and toincrease the clearance of LDL cholesterol.

International Patent Application Number PCT/EP00/06668 concerns thenovel use of the SREBP-cleavage activating protein (SCAP) in a screeningmethod. Two compounds are disclosed, namely4-(4-chloro-benzoylamino)-N-4-[4-(2-ethoxy-4-ethyl-phenyl)-piperidin-1-yl]-butyl)benzamideand4-(4-benzoyl)-N-4-[4-(4-isopropyl-2-methoxy-phenyl)-piperidin-1-yl]-butyl)benzamidehydrochloride, which do not form part of the present invention.

Another publication, Bioorganic and Medicinal Chemistry Letters Vol. 5,3, 219-222, 1995 discloses compounds having the general formula (A)

where X may be COMe, SO₂Me and NH₂, as having high affinity for thedopamine D₃ receptor and postulates their use in CNS disorders,particularly psychiatric illness. The compound of formula A where X isCOMe is also disclosed in J. Pharmacol. Exp. Ther. 287; 1 1998 187-197and Bioorganic and Medicinal Chemistry Letters Vol. 7, 15, 1995-1998,1997, again as being useful in treating CNS disorders. It will be notedthat the present invention differs from the compounds of formula (A) inuse of a piperidine ring rather than a piperazine and in the utilitydisclosed.

Journal Of Medicinal Chemistry, Vol. 40, 6, 952-960,1997 disclosescompounds of formula (B)

where m=0, 1 or 2; n=2 or 3; R¹ and R³=H or OMe and R² may be Ph, asselective 5-HT_(1A) receptor ligands having CNS activity. It will benoted that the examples of the present invention differ from those offormula (B) in use of a piperidine ring rather than a piperazine and inthe utility disclosed.

International Patent Application Publication Number WO99/45925 disclosescompounds of formula (C)

where R¹ may be hydrogen, R² may be hydrogen and R³ may be a group

where X may be an aryl group and n may be 1. Specifically disclosed arecompounds where the group COR³ is formed from 2- and 4-biphenylcarboxylic acid and R¹ and R² are methyl or hydrogen respectively. Theutility of the compounds is as opioid receptor binding agents which maybe useful as analgesics. The substitution on the 3- and 4-positions ofthe piperidine ring leave the compounds of this publication outside thescope of the present invention. Furthermore, the utility disclosed isdifferent.

International Patent Application Publication Number WO98/37893 disclosescompounds of formula (D)

where Ar may represent an optionally substituted phenyl or naphthyl, Gmay be N or CH₂ (sic), W may be an optionally substituted alkylene, Ymay be hydrogen and Z may represent a group R⁴CONRr, where R⁴ may be anoptionally substituted phenyl and R₅ may be hydrogen. These compoundsare described as being D2 receptor antagonists useful in the treatmentof CNS disorders such as Parkinson's Disease. None of the compoundsspecifically disclosed fall within the scope of the present inventionand the disclosed utlity is different.

International Patent Application Publication Number WO9402473 disclosescompounds of formula (E)

where A is —NHCO— or —CONH—; R₁-R₅ may be hydrogen or phenyl, m may be1-3 and n may be 1-3. Specifically disclosed are the followingcompounds: No. A n m R¹ R² R³ R⁴ R⁵ 5 NHCO 2 1 H H Ph H H 12 NHCO 2 2 HH Ph H H 19 NHCO 2 3 H H Ph H H

The compounds are described as 5HT-1A agonists having CNS activity andmay be used as anti-depressants, anti-hypertensive, analgesics etc. Itwill be noted that the examples of the present invention differ fromthose of formula (E) in use of a piperidine ring rather than apiperazine and in the utility disclosed.

International Patent Application Publication Number WO99/45925 disclosescompounds of formula (F)

where A may represent a substituted phenyl group, W represents a linearor branched alkylene group having from 2 to 6 carbon atoms; Y mayrepresent a group NHCO or CONH; and R may be a substituted phenyl group.Particularly disclosed is the compound G

These compounds are described as being α1A-adrenergic receptors usefulin the treatment of contractions of the prostate, urethra and lowerurinary tract, without affecting blood pressure. It will be noted thatthe examples of the present invention differ from those of formula (G)in use of a piperidine ring rather than a piperazine and in the utilitydisclosed.

International Patent Application Publication Number WO98/35957 describescompounds of formula (H)

wherein R¹-R⁵ are each individually selected from the group ofsubstituents including hydrogen, halogen, hydroxyl, thiol, lower alkyl,substituted lower alkyl, alkenyl, alkynyl, alkylalkenyl, alkylalkynyl,alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl,substituted aryl, heterocycle, heteroaryl, substituted heterocycle,heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl,alkylcycloheteroalkyl, nitro and cyano. Specifically disclosed compoundsare those formed by the N-alkylation of a a substituted piperidine orpiperazine with a group (J)

where X is a leaving group. None of the compounds specifically disclosedfall within the scope of the present invention and the invention is inno way suggested by the disclosure. The compounds are said to be of useas NPY Y5 receptor antagonists in the treatment of obesity, bulemia andrelated disorders and NPY Y5 receptor inhibition related disorders suchas memory disorders, epilepsy, dyslipidemia and depression.

Journal Of Medicinal Chemistry, Vol. 31, 1968-1971, 1988 disclosescertain aryl piperazines compounds, which fall outside the presentinvention, as 5HT-1a Serotonin Ligands as potential CNS agents.Specifically disclosed are compounds of formula (K)

where Ar=Ph and R=Ph, Ar=2-methoxyphenyl and R=Ph and Ar=2-pyrimidyl andR=Ph.

Journal Of Medicinal Chemistry, Vol. 34, 2633-2638, 1991 discloses arylpiperazines having reduced al adrenergic affinity. Specificallydisclosed is the compound (L)

where R is 4-(BnO)-phenyl, which falls outside the scope of the presentinvention.

The present invention provides aryl piperidine derivatives which areparticularly useful in treating cardiovascular disorders associated withelevated levels of circulating LDL-cholesterol.

According to a first aspect, the invention provides a compound offormula (I)

wherein

-   Ar₁ is:-   (i) phenyl, naphthyl or phenyl fused by a C₃₋₈ cycloalkyl; or-   (ii) heterocyclyl selected from the list consisting of: monocyclic    radicals and fused polycyclic radicals, wherein said radicals    contain a total of from 5-14 ring atoms, wherein said radicals    contain a total of from 1-4 ring heteroatoms independently selected    from oxygen, nitrogen and sulfur, and wherein individual rings of    said radicals may be independently saturated, partially unsaturated    or aromatic, provided that at least one ring is aromatic;    -   where Ar₁ is independently substituted by at least one R¹ group        and is independently substituted by 0-3 R³ groups;-   Ar₂ is a phenyl group, a 5-6 membered heteroaromatic group or a    bicyclic heteroaromatic group, each of which are optionally    substituted by 1-4 groups independently selected from the list:    C₁₋₄-allyl, halogen, hydroxy, C₁-alkoxy, C₁₋₆-acyl, C₁₋₆-acyloxy,    amino, C₁₋₄alkylamino, di-C₁₋₄alkylamino, —(CH₂)_(n)OH,    —(CH₂)_(n)NR_(x)R_(y), —O(CH₂)_(n)O(CH₂)_(m)OR²,    —O(CH₂)_(n)C(O)NR_(x)R_(y), —O(CH₂)_(n)CN, C₂ alkenyl,    —O(CH₂)_(n)CO₂R², —OSO₂(CH₂)_(p)CH₃, —OSO₂NR_(x)R_(y) and    —CO₂(CH₂)_(p)CH₃;-   Ar₃ is:-   (i) phenyl, naphthyl or phenyl fused by a C₃₋₈cycloalkyl; or-   (ii) heterocyclyl selected from the group consisting of monocyclic    radicals and fused polycyclic radicals, wherein said radicals    contain a total of from 5-14 ring atoms, wherein said radicals    contain a total of from 1-4 ring heteroatoms independently selected    from oxygen, nitrogen and sulfur, and wherein individual rings of    said radicals may be independently saturated, partially unsaturated,    or aromatic, providing that at least one ring is aromatic;    -   wherein Ar₃ is optionally substituted by 1-4 groups        independently selected from the group consisting of: hydroxy,        C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkenyloxy,        C₁₋₄perfluoroalkoxy, C₁₋₄alkylsulfonylamino (such as —NHSO₂CH₃,        —NHSO₂CH(CH₃)₂), fluoroC₁₋₄alkylsulfonylamino (such as        —NHSO₂CH₂CF₃), C₁₋₄alkylcarbonylamino,        fluoroC₁₋₄alkylcarbonylamino, halogen (such as chlorine),        nitrile, nitro, C₁₋₄perfluoroalkyl, C₁₋₄alkylcarbonyl,        fluoroC₁₋₄alkylcarbonyl, C₁₋₄alkoxycarbonyl, aminocarbonyl,        C₁₋₄alkylaminocarbonyl, di-C₁₋₄alkylaminocarbonyl,        C₁₋₄alkylsulfonyl, C₁₋₄alkylaminosulfonyl,        di-C₁₋₄alkylaminosulfonyl, C₁₋₄alkylsulfonyl and        C₁₋₄alkylsulfoxy;-   E is —C₁₋₆alkylene-;-   X is —CONR²— or —NR²CO—;    wherein-   R¹ is O(CH₂)_(n)OR²;-   R² is C₁₋₄alkyl or hydrogen;-   R³ is halogen, C₁₋₄alkoxy or C₁₋₄alkyl;-   R_(x) and R_(y) are independently C₁₋₄alkyl or hydrogen;-   n and m are independently 1-4; and-   p is 0-4;    or a physiologically acceptable prodrug, salt or solvate thereof.

Referring to the general formula (I), alkyl, alkylene and alkoxy includeboth straight and branched chain saturated hydrocarbon groups. Examplesof alkyl groups include methyl and ethyl groups, examples of alkylenegroups include methylene and ethylene groups, whilst examples of alkoxygroups include methoxy and ethoxy groups.

Referring to the general formula (I), alkenyl includes both straight andbranched chain saturated hydrocarbon groups containing one double bond.Examples of alkenyl groups include ethenyl or n-propenyl groups.

Referring to the general formula (I), acyl refers to aliphatic or cyclichydrocarbons attached to a carbonyl group through which the substituentbonds, such as acetyl.

Referring to the general formula (I), phenyl fused by a C₃₋₈cycloalkylincludes bicyclic rings such as 1,2,3,4-tetrahydronaphthyl, which, forthe avoidance of doubt, is linked to the rest of the molecule throughthe aromatic ring.

Referring to general formula (I), a halogen atom includes fluorine,chlorine, bromine or iodine.

Referring to the general formula (I), C₁₋₃-perfluoroalkyl andC₁₋₃perfluoroalkoxy includes compounds in which the hydrogens have beenpartially or fully replaced by fluorines, such as trifluoromethyl andtrifluoromethoxy or trifluoroethyl.

Referring to the general formula (I), a 5-6 membered heteroaromaticgroup includes a single aromatic ring system containing at least onering heteroatom examples include pyridyl and thiazolyl.

Referring to the general formula (I), a 3-7 membered heterocyclyl groupmeans any single ring system containing at least one ring heteroatomindependently selected from O, N and S, wherein said ring is saturated,unsaturated or aromatic.

Preferably Ar₁ is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indolyl,benzofuranyl, benzothiophenyl or indazolyl. More preferably Are isphenyl or 1,2,3,4-tetrahydronaphthyl. Most preferably Are is1,2,3,4-tetrahydronaphthyl.

Where Ar₁ is 1,2,3,4-tetrahydronaphthyl, the link to the piperidine ringis preferably through the 2-position of the 1,2,3,4-tetrahydronaphthylmoiety and mono-substitution by R¹ is in the corresponding 1-position.

Preferably E is n-butylene.

Preferably X is —NR²CO—. Preferably R² is hydrogen.

Preferably Ar₂ is phenyl or a 5-6-membered heteroaromatic group. Morepreferably Ar₂ is phenyl, pyridyl, thiazolyl, oxazolyl or imidazolyl.More preferably Ar₂ is phenyl, oxazolyl or thiazolyl.

Preferably Ar₃ is phenyl, pyridyl or thienyl, more preferably phenyl.Preferably Ar₃ is substituted by halogen (e.g. chloro),C₁₋₄perfluoroalkyl (e.g. trifluoromethyl), nitrile, C₁₋₄acyl (e.g.acetyl), C₁₋₄alkylsulfonyl (e.g. methylsulfonyl) orC₁₋₄alkylsulfonylamino.

When Ar₃ is phenyl, para-substitution is preferred.

Preferably R¹ is OCH₂CH₂OR².

Preferably Ar₁ is not substituted by R³, however when Ar₁ is substitutedby R³ preferred substituents are C₁₋₄alkyl or C₁₋₄alkoxy.

Preferably Ar₂ is optionally substituted by C₁₋₄alkyl, halogen, hydroxy,hydroxyC₁₋₄alkyl or C₁₋₄alkoxy. Preferably Ar₂ is optionally substitutedby C₁₋₄alkyl or hydroxyC₁₋₄alkyl.

Particularly preferred compounds of the invention include those in whicheach variable in Formula (I) is selected from the preferred groups foreach variable. Even more preferable compounds of the invention includethose where each variable in Formula (I) is selected from the morepreferred or most preferred groups for each variable.

Preferably

-   Ar₁ is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indolyl,    benzofuranyl, benzothiophenyl or indazolyl; where Ar₁ is    independently substituted by at least one R¹ group and is    independently substituted by 0-3 R³ groups;-   Ar₂ is phenyl, pyridyl, thiazolyl, oxazolyl or imidazolyl, each of    which are optionally substituted by 14 groups independently selected    from the list; C₁₋₄alkyl, halogen, hydroxy, hydroxyC₁₋₄alkyl and    C₁₋₄alkoxy;-   Ar₃ is phenyl, pyridyl or thienyl, wherein Ar₃ is optionally    substituted by 1-4 groups independently selected from the group    consisting of: halogen (e.g. chloro), C₁₋₄perfluoroalkyl (e.g.    trifluoromethyl), nitrile, C₁₋₄acyl (e.g. acetyl), C₁₋₄alkylsulfonyl    (e.g. methylsulfonyl) and C₁₋₄alkylsulfonylamino;-   E is n-butylene;-   X is —NR²CO—;    wherein-   R¹ is —OCH₂CH₂OR²;-   R² is C₁₋₄alkyl or hydrogen;-   R³ is halogen, C₁₋₄alkoxy or C₁₋₄alkyl; and-   n is 1-4.

Preferred compounds of formula (I) are selected from the list:

-   4-Hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic    acid    (4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide    (Example 3);-   4′-Cyano-biphenyl-4-carboxylic acid    (4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl)butyl)-amide    hydrochloride (Example 5);-   2-(4-Cyano-phenyl)-4-methyl-thiazole-5-carboxylic acid    (4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide,    hydrochloride (Example 7);-   2-(2,4-dichloro-phenyl)-4-methyl-thiazole-5-carboxylic acid    (4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide    (Example 8);-   2′,4′-Chloro-biphenyl-4-carboxylic acid    (4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide    (Example 9);-   4′-Chloro-biphenyl-4-carboxylic acid    (4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide    (Example 10); and-   4′-Methanesulfonylamino-biphenyl-4-carboxylic acid    (4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide    (Example 12).

For the avoidance of doubt, unless otherwise indicated, the termsubstituted means substituted by one or more defined groups. In the casewhere groups may be selected from a number of alternative groups, theselected groups may be the same or different.

For the avoidance of doubt, the term independently means that where morethan one substituent is selected from a number of possible substituents,those substituents may be the same or different.

As used herein the term ‘physiologically acceptable’ means a compoundwhich is suitable for pharmaceutical use.

Suitable physiologically acceptable salts of the compounds of generalformula (I) include acid addition salts formed with pharmaceuticallyacceptable inorganic acids for example, phosphates, hydrochlorides,hydrobromides or sulphates, or with pharmaceutically acceptable organicacids for example mesylates, lactates and acetates. More suitably, aphysiologically acceptable salt of the compounds of general formula (I)is a phosphate salt.

The solvates may, for example, be hydrates.

In addition, prodrugs are also included within the context of thisinvention. Prodrugs are any covalently bonded carriers that release acompound of structure (I) in vivo when such prodrug is administered to apatient. Prodrugs are generally prepared by modifying functional groupsin a way such that the modification is cleaved, either by routinemanipulation or in vivo, yielding the parent compound. Prodrugs include,for example, compounds of this invention wherein hydroxy, amine orsulfhydryl groups are bonded to any group that, when administered to apatient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus,representative examples of prodrugs include (but are not limited to)acetate, formate and benzoate derivatives of alcohol, sulfhydryl andamine functional groups of the compounds of formula (I). Further, in thecase of a carboxylic acid (—COOH), esters may be employed, such asmethyl esters, ethyl esters, and the like.

Hereinafter, compounds, their pharmaceutically acceptable salts, theirsolvates and polymorphs, defined in any aspect of the invention (exceptintermediate compounds in chemical processes) are referred to as“compounds of the invention”.

Compounds of the invention may be administered as the raw chemical butthe active ingredient is preferably presented as a pharmaceuticalformulation.

Compounds of the invention may be formulated for oral, buccal,parenteral, transdermal, topical (including ophthalmic and nasal), depotor rectal administration or in a form suitable for administration byinhalation or insufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

For transdermal administration the compounds of the invention may beformulated as creams, gels, ointments or lotions or as a transdermalpatch. Such compositions may for example be formulated with an aqueousor oily base with the addition of suitable thickening, gelling,emulsifying, stabilising, dispersing, suspending, and/or colouringagents.

The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunit dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

The compositions may contain from 0.1% upwards, e.g. 0.1-99% of theactive material, depending on the method of administration. A proposeddose of the compounds of the invention is 0.25 mg/kg to about 125 mg/kgbodyweight per day e.g. 20 mg/kg to 100 mg/kg per day. It will beappreciated that it may be necessary to make routine variations to thedosage, depending on the age and condition of the patient and theprecise dosage will be ultimately at the discretion of the attendantphysician or veterinarian. The dosage will also depend on the route ofadministration and the particular compound selected.

The compounds of the invention may, if desired, be administered with oneor more therapeutic agents and formulated for administration by anyconvenient route in a conventional manner. Appropriate doses will bereadily appreciated by those skilled in the art. For example, thecompounds of the invention may be administered in combination with anHMG CoA reductase inhibitor, an agent for inhibition of bile acidtransport or fibrates.

The compounds of the invention are inducers of LDL-r expression and arethus of use in the treatment of conditions resulting from elevatedcirculating levels of LDL-cholesterol. Thus compounds of the inventionare of use in the treatment of diseases in which lipid imbalance isimportant, e.g. atherosclerosis, pancreatitis, non-insulin dependentdiabetes mellitus (NIDDM), coronary heart diseases and obesity. Inaddition compounds of the invention are also useful in lowering serumlipid levels, cholesterol and/or triglycerides, and are of use in thetreatment of hyperlipemia, hyperlipidemia, hyperlipoproteinemia,hypercholesterolemia and/or hypertriglyceridemia.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.

Compounds of the invention may be prepared in a variety of ways. In thefollowing reaction schemes and hereafter, unless otherwise stated groupsAr₁, Ar₂, Ar₃, R¹, R², R³, R⁴, E and X are as defined in the firstaspect. These processes form further aspects of the invention.

Throughout the specification, general formulae are designated by Romannumerals (I), (II), (III), (IV) etc. Subsets of these general formulaeare defined as (Ia), (Ib), (Ic) etc. . . . (IVa), (IVb), (IVc) etc.

Compounds of formula (Ia), i.e. compounds of formula (I) where X is—NR²C(O)— where the nitrogen is attached to E, may be prepared accordingto reaction scheme 1 by reacting compounds of formula (II) withcompounds of formula (III) where L is a leaving group such as halogen orhydroxy, using standard amide coupling conditions detailed in theexperimental section.

Compounds of formula (Ib), i.e. compounds of formula (I) where R¹ is—OR, may be prepared from the corresponding hydroxy compound (IV)according to reaction scheme 2. Preferred reaction conditions comprisetreating (IV) with a suitable base such as sodium hydride or caesiumcarbonate followed by addition of RL where L is a leaving group such ashalogen. Compounds of formula (IV) may be prepared by adapting methodsdescribed herein for the preparation of compounds of formula (I).

Compounds of formula (I) where Ar₁ is a nitrogen containing heterocyclemay be substituted on the nitrogen by nucleophilic substitution. Forinstance where Ar₁ is indol-3-yl, substitution may be effected bytreating (I) with base such as sodium hydride followed by reaction witha suitable nucleophile.

Compounds of formula (I) may be prepared be coupling boronic acidcompounds of formula (V) with compounds of formula (VI) according toreaction scheme 3. Preferred reaction conditions comprise treatment withPd(PPh₃)₄ and a suitable base such as sodium carbonate at elevatedtemperature.

Compounds of formula (Ic) may be prepared by removal of protection groupP frrom compounds of formula (XI) according to reaction scheme 4. Apreferred protecting group P is tetrahydropyran-2-yl which may be beremoved by acid hydrolysis, typicially reaction with dilute hydrochloricacid in methanol at room temperature.

Compounds of formula (XI) may be prepared by adapting methods describedherein for the preparation of compounds of formula (I).

Compounds of formula (II) may be prepared according to reaction scheme 5by reacting a compound of formula (VII) with a compound of formula(VIII) where L is a leaving group such as halogen and P is a suitableprotecting group. Preferred conditions comprise reaction with a suitablebase such as potassium carbonate. Removal of protecting group P givescompounds of formula (II). A preferred nitrogen protecting group iswhere the nitrogen attached to E and group R² form phthalimide (i.e.1,3-dioxo-1,3-dihydro-isoindol-2-yl). Removal of the phthalimideprotecting group gives compounds of formula (II) where R² is hydrogen.Preferred conditions comprise treatment with hydrazine at elevatedtemperature.

Compounds of formula (VII) may be prepared by methods described in theexperimental section hereinbelow. Compounds of formula (VIII) are eitherknown or may be prepared from known compounds by methods available tothe skilled person.

Compounds of formula (IIIa), i.e. compounds of formula (III) (seereaction scheme 1) where L is hydroxy, may be prepared according toreaction scheme 5 by coupling boronic acid compounds of formula (IX)with compounds of formula (X) where L is a leaving group such as halogenunder analogous conditions described for reaction scheme 3.

Compounds of formula (IX) and (X) are either known or may be preparedfrom known compounds by methods available to the skilled person.

The protecting groups used in the preparation of compounds of formula(I) may be used in conventional manner. See for example ‘ProtectiveGroups in Organic Chemistry’ Ed. J. F. W. McOmie (Plenum Press 1973) or‘Protective Groups in Organic Synthesis’ by Theodora W Greene and P M GWuts (John Wiley and Sons 1991). Conventional amino protecting groupsmay include for example aralkyl groups, such as benzyl, diphenylmethylor triphenylmethyl groups; and acyl groups such as N-benzyloxycarbonylor t-butoxycarbonyl. Conventional carboxylic acid protecting groupsinclude methyl and ethyl groups.

It will be appreciated that the invention includes the following furtheraspects. The preferred embodiments described for the first aspect extendthese further aspects:

i) a pharmaceutical composition comprising a compound of the inventionand a pharmaceutically acceptable carrier or diluent;

ii) the use of a compound of the invention in the manufacture of amedicament for use in the treatment of conditions resulting fromelevated circulating levels of LDL-cholesterol;

iii) the use of a compound of the invention in the manufacture of amedicament for the treatment or prophylaxis of a disorder in which lipidimbalance is important (such as atherosclerosis, pancreatitis,non-insulin dependent diabetes mellitus (NIDDM), coronary heart diseasesand obesity);

iv) the use of a compound of the invention in the manufacture of amedicament for lowering serum lipid levels, cholesterol and/ortriglycerides;

v) the use of a compound of the invention in the manufacture of amedicament for the treatment or prophylaxis of hyperlipemia,hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and/orhypertriglyceridemia;

vi) a compound of the invention for use as a medicament;

vii) a method of treatment or prophylaxis of a disorder resulting fromelevated circulating levels of LDL-cholesterol in a human patientcomprising administering to the human an effective amount of a compoundof the invention;

viii) a method of lowering serum lipid levels, cholesterol and/ortriglycerides in a human patient comprising administering to the humanan effective amount of a compound of the invention; and

ix) a combination of a compound of the invention with an HMG CoAreductase inhibitor, an agent for inhibition of bile acid transport or afibrate.

According to a further aspect, the invention provides a compound offormula (I)

wherein

-   Ar₁ represents    -   (i) phenyl, naphthyl, or phenyl fused by a C₃₋₈cycloalkyl, or    -   (ii) heterocyclyl selected from the group consisting of        monocyclic radicals and fused polycyclic radicals, wherein said        radicals contain a total of from 5-14 ring atoms, wherein said        radicals contain a total of from 1-4 ring heteroatoms        independently selected from oxygen, nitrogen and sulfur, and        wherein individual rings of said radicals may be independently        saturated, partially unsaturated, or aromatic, provided that at        least one ring is aromatic,        where Ar₁ bears at least one group independently represented by        R¹ and 0-3 groups independently represented by R³;-   R¹ is O(CH₂)_(n)OR²;-   R² is H or (CH₂)_(m)CH₃;-   n is 1-4;-   m is 0-4;-   R³ is selected from halogen, —O—(C₀₋₄ alkylene)-R⁴ or    —(C₀₋₄alkylene)-R⁴, where each alkylene group may additionally    incorporate an oxygen in the chain, with the proviso that there are    at least two carbon atoms between any chain heteroatoms;-   R⁴ represents    -   (i) hydrogen, C₁₋₄ perfluoroalkyl, C₁₋₄perfluoroalkoxy,    -   (ii) phenyl, phenyl fused by a C₃₋₈ cycloalkyl, naphthyl or a 5-        or 6-membered heteroaromatic group, optionally substituted by        one or two groups independently selected from halogen, C₁₋₄        alkyl, hydroxy, C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino and di-C₁₋₄        alkylamino,    -   (iii) C₃₋₈cycloalkyl or a monocyclic heterocyclyl radical        containing a total of 3-7 ring atoms, wherein said radical        contains a total of from 1-4 ring heteroatoms independently        selected from oxygen, nitrogen and sulfur, wherein said radical        may be independently saturated, partially unsaturated, or        aromatic, and where the C₃₋₈cycloalkyl or a monocyclic        heterocyclyl may bear one or two groups independently selected        from halogen, C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, amino, C₁₋₄        alkylamino and di-CIA alkylamino, or    -   (iv) amino, C₁₋₄ alkylamino or di-C₁₋₄alkylamino;-   Ar₂ represents phenyl or a 5-6 membered heteroaromatic group or a    bicyclic heteroaromatic group, where each group is optionally    substituted by one or two groups independently selected from the    group consisting of: C₁₋₄ alkyl, halogen, hydroxy, C₁₋₄ alkoxy, C₁    acyl, C₁₋₆ acyloxy, amino, C₁₋₄ alkylamino and di-C₁₋₄ alkylamino    groups;-   Ar₃ represents    -   (i) phenyl, naphthyl, or phenyl fused by a C₃₋₈cycloalkyl,    -   (ii) heterocyclyl selected from the group consisting of        monocyclic radicals and fused polycyclic radicals, wherein said        radicals contain a total of from 5-14 ring atoms, wherein said        radicals contain a total of from 1-4 ring heteroatoms        independently selected from oxygen, nitrogen and sulfur, and        wherein individual rings of said radicals may be independently        saturated, partially unsaturated, or aromatic, providing that at        least one ring is aromatic,-   where Ar₃ is optionally substituted by 1-4 groups independently    selected from the group consisting of: hydroxy, alkyl, C₁₋₄ alkoxy,    C₂₋₄ alkenyl, C₂₋₄ alkenyloxy, C₁₋₄perfluoroalkoxy, C₁₋₄ acylamino    or an electron withdrawing group selected from the list consisting    of: nitrile, nitro, C₁₋₄, C₁₋₄ perfluoroalkyl, C₁₋₄ acyl, C₁₋₄    alkoxycarbonyl, aminocarbonyl, C₁₋₄alkylaminocarbonyl; di-C₁₋₄    alkylaminocarbonyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylaminosulfonyl and    di-C₁₋₄ alkylaminosulfonyl, C₁₋₄ alkylsulfonyl and C₁₋₄alkylsulfoxy;-   E represents —C₁₋₆ alkylene-;-   X represents —CON(H or C₁₋₄alkyl)- or —N(H or C₁₋₄alkyl)CO—; or a    physiologically acceptable prodrug, salt or solvate thereof.

The invention is further described with reference to the followingnon-limiting examples.

Abbreviations:

Pd(PPh₃)₄—Tetrakis-(triphenylphosphine)-palladium(0),THF—Tetrahydrofuran, BF₃-Et₂O—Boron trifluoride diethyl etherate,DCM—Dichloromethane, TEA—triethylamine, CH₃CN—Acetonitrile,EtOH—Ethanol, EtOAc—Ethyl acetate, iPr₂O—Di-isopropyl ether,iPrOH—Isopropanol, Pd/C—Palladium on carbon, Et₂O— diethyl ether,Chex—cyclohexane, MeOH—Methanol, DMF—Dimethyl formamide, DME—Ethyleneglycol dimethyl ether, EDCl—1-(3-dimethylaminopropyl)-,ethylcarbodiimide hydrochloride, HOBt—1-Hydroxybenzotriazole, rt—Roomtemperature, AcOH—Acetic acid, NaOH—Sodium hydroxide, KOH—potassiumhydroxide, LiOH, H₂O—lithium hydroxide monohydrate, HCl—Hydrochloricacid, AcOH—Acetic acid, NaH—Sodium hydride, Na₂SO₄—Sodium sulfate,CCl₄—Carbon tetrachloride, AlBN—2,2′-Azobis(2-methylpropionitrile),K₂CO₃—Potassium carbonate, Na₂CO₃—Sodium carbonate, NaCl—Sodiumchloride, Cs₂CO₃—Cesium carbonate, CrO₃—Chromium(VI) oxide, BBr₃—Borontribromide, P₄S₁₀—Phosphorus sulfide.

Intermediate 1:1-[4-(1-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethanone

To a solution of 5,6,7,8-tetrahydro-naphthalen-1-ol (20.0 g, 0.135 mol)and 1-acetyl-4-piperidone (22.84 g, 1.2 eq.) in THF (400 mL), was addeddropwise BF₃-Et₂O (68 mL, 4.0 eq). The mixture was stirred at 100° C.for 2 hours, and 14 hours at room temperature. The mixture was treatedwith a 1N HCl solution (400 mL). The resulting solution was extractedwith DCM. The organic layer was dried over Na₂SO₄ and evaporated todryness to give an oil which was recrystallized in acetonitrile to givethe title compound (24.2 g, 89 mmol) as a white crystals in a 66% yield;GC/MS: M+C₁₇H₂₀NO₂ 271.

Intermediate 2:1-[4-(1-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-yl]-ethanone

To a solution of intermediate 1 (9.4 g, 34.7 mmol) in EtOH (300 mL) wasadded Pd/C, 10% (0.9 g) and the reaction mixture was stirred under anatmospheric pressure of hydrogen at 25° C. for 24 hours. The mixture wasfiltered through a bed of celite. The filtrate was evaporated underreduced pressure to give the title compound (9.6 g, 35 mmol) as a whitefoam; GC/MS: M⁺C₁₇H₂₂NO₂ 273.

Intermediate 3:1-[4-(4-Ethyl-2-hydroxy-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethanone

The same method was employed as in the preparation of intermediate 1 butstarting from 3-ethyl-phenol and gave the title compound as a pink solidin a quantitative yield; GC/MS: M⁺ C₁₅H₁₉NO₂ 245.

Intermediate 4: 1-[4-(4-Ethyl-2-hydroxy-phenyl)-piperidin-1-yl]-ethanone

The same method was employed as in the preparation of intermediate 2 butstarting from intermediate 3 and gave the title compound as a solid in a89% yield; GC/MS: M⁺ C₁₅H₂₁NO₂ 247.

Intermediate 5:1-(4-{4-Ethyl-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-piperidin-1-yl)-ethanone

To a solution of intermediate 4 (5 g, 20 mmol) in acetone (200 mL) wasadded K₂CO₃ (5.52 g, 2 eq.) and 2-(2-bromo-ethoxy)-tetrahydropyran (4.58mL, 1.5 eq.). The mixture was stirred at reflux for 48 hours and thesolvent evaporated. The residue was diluted in DCM and washed withwater. The organic layer was dried over Na₂SO₄ and filtered to give thetitle compound (11.0 g, 27 mmol) as a yellow oil in a quantitative yieldafter chromatography using DCM/MeOH (98/02) as eluent; GC/MS: M⁺C₂₂H₃₃NO₄ 290 (M-Tetrahydropyran).

Intermediate 6:4-{4-Ethyl-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-piperidine

To a solution of intermediate 5 (1.0 eq) in EtOH was added a NaOH/H₂O(1/1) solution and the mixture was stirred to reflux for 24 hours. Thesolvent was evaporated, water added and the residue extracted with DCM.The organic layer was dried over Na₂SO₄ and the solvent evaporated togive the title compound as a brown oil; GC/MS: M⁺ C₂₀H₃₁NO₃ 333.

Intermediate 7:2-[4-(4-{4-Ethyl-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-piperidin-1-yl)-butyl]-isoindole-1,3-dione

To a solution of intermediate 6 (1.0 eq) in acetone was added K₂CO₃ (2.0eq.) and 4 bromobutyl-phthalimide (1.0 eq.) and the mixture was stirredat reflux for 6 hours. he mixture was filtered, the filtrate wasevaporated and the residue was purified by flash chromatography usingDCM/MeOH (95/05) as eluent to give the title compound as a brown oil ina quantitative yield; ¹H NMR (CDCl₃, 300 MHz)

7.8 (m, 2H), 7.6 (m, 2H), 7 (d, 1H), 6.6 (d, 1H), 6.5 (s, 1H), 5.2 (s,2H), 4.8 (m, 1H), 4.1-1.1 (m, 32H).

Intermediate 8:4-(4-{4-Ethyl-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-piperidin-1-yl)-butylamine

A solution of intermediate 7 (1.0 eq) in MeOH was treated with hydrazinemonohydrate (2.0 eq.) and the resulting mixture was stirred to refluxfor 16 hours. After cooling to rt and evaporation under reducedpressure, the residue was taken up in water and 1N HCl solution wasadded until pH=4. Filtration gave yellow solution that was treated witha concentrated NaOH solution. Extraction with DCM, drying over Na₂SO₄and filtration gave the title compound as a brown oil in a 78% yield; ¹HNMR (CDCl₃, 300 MHz) δ 7.1 (d, 1H), 6.7 (d, 1H), 6.6 (s, 1H), 5.2 (s,2H), 4.8 (m, 1H), 4.1-1.1 (m, 34H)

Intermediate 9: 4′-Trifluoromethyl-biphenyl-4-carboxylic acid[4-(4-(4-{4-ethyl-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-piperidin-1-yl)-butyl]-amide

A solution of intermediate 8 (1.0 eq) in DMF was treated with4′-trifluoromethyl-biphenyl-4-carboxylic acid (1.0 eq.), EDCl (1.5 eq.),HOBT (1.5 eq.) and TEA (1.5 eq.) and the mixture stirred for 24 hours atrt. The solvent was evaporated, and the residue was diluted with DCM andwashed with water and with a 1N NaOH solution. The organic layer wasdried over Na₂SO₄ and evaporated. After purification by flashchromatography using DCM/MeOH (95/5) as eluent, the title compound wasobtained as white crystals in a 27% yield; LC/MS: M+H C₃₈H₄₈F₃N₂O₄ 653.

Intermediate 10: 4′-Cyano-biphenyl-4-carboxylic acid[4-(4-{4-ethyl-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}piperidin-1-yl)-butyl]-amide

The same method was employed as in the preparation of intermediate 9 butstarting from the available 4′-cyano-biphenyl-4-carboxylic acid and gavethe title compound as a yellow oil in a 20% yield; LC/MS: M+H C₃₈H₄₈N₃O₄610.

Intermediate 11:1-(4-{1-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-2-yl}-piperidin-1-yl)ethanone

The same method was employed as in the preparation of intermediate 5 butstarting from intermediate 2 and gave the title compound as a yellow oilin a 95% yield; LC/MS: M+H C₂₄H₃₆NO₄ 402.

Intermediate 12:4-{1-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-2-yl}-piperidine

The same method was employed as in the preparation of intermediate 6 butstarting from intermediate 11 and gave the title compound as a yellowoil in a quantitative yield; LC/MS: M+H C₂₂H₃₄NO₃ 360.

Intermediate 13:2-[4-(4-(4-{1-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-2-yl}-piperidin-1-yl)-butyl}-isoindole-1,3-dione

The same method was employed as in the preparation of intermediate 7 butstarting from intermediate 12 and gave the title compound as a yellowoil in a 93% yield; LC/MS: M+H C₃₄H₄₅N₂O₅ 561.

Intermediate 14:4-(4-{1-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-2-yl}-piperidin-1-yl)-butylamine

The same method was employed as in the preparation of intermediate 8 butstarting from intermediate 13 and gave the title compound as a yellowoil (contained 30% of formed pyridazine dione); LC/MS: M+HC₂₆H₄₃N₂O₃431.

Intermediate 15: 4-Trifluoromethyl-thiobenzamide

A solution of α,α,α-trifluoro-p-tolunitrile (603.5 g, 3.53 mol) in dryDMF (2 L) under N₂ was heated at 70° C. and the thioacetamide (505 g,1.9 eq.) was added. The reaction mixture was treated with HCl gas for 15minutes and stirred at 95° C. for 6 hours. This treatment was repeated 3times and the mixture stirred at rt for 24 hours. After cooling at 0°C., water was added and the residue extracted with diethyl ether (4 L).The organic layer was washed with water (3 L), dried over Na₂SO₄ and thesolvent evaporated. The brownish powder was washed with pentane (3 L) togive the title compound (530.3 g, 2.59 mol) as a brown solid in a 73%yield; GC/MS: M⁺ C₈H₆F₃NS 205.

Intermediate 16:4-Methyl-2-(4-trifluoramethyl-phenyl)-thiazole-5-carboxylic acid ethylester

To a solution of intermediate 15 (530.3 g, 2.59 mol) in EtOH (2.6 L) wasadded 2-chloro-3-oxo-butyric acid ethyl ester (465 mL, 1.3 eq.) and themixture was stirred at rt for 7 hours and at 70° C. for 14 hours. Aftercooling at 0° C., the precipitate was filtered and washed with cold EtOH(500 mL) to give the title compound (573.0 g, 1.89 mol) as a beigepowder in a 73% yield; ¹H NMR (CDCl₃, 300 MHz)

7.9 (d, 2H), 7.6 (d, 2H), 4.3 (q, 2H), 2.65 (s, 3H), 1.25 (t, 3H).

Intermediate 17:4-Bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidethyl ester

To a solution of intermediate 16 (15.75 g, 50.0 mmol) in CCl₄ was addedslowly N-bromosuccinimide (8.9 g, 1.1 eq.) and AlBN (1 g, 10% mol) andthe mixture was stirred at 80° C. for 3 hours. The mixture was filteredand the filtrate evaporated. After purification by flash chromatography,using DCM/Cyclohexane (60/40) as eluent, the title compound (4.9 g, 12.5mmol) was obtained as white solid in a 25% yield. ¹H NMR (CDCl₃, 300MHz)

8.2 (d, 2H), 7.8 (d, 2H), 5.1 (s, 2H), 4.5 (q, 2H), 1.3 (t, 3H)

Intermediate 18:4-Acetoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidethyl ester

To a solution of intermediate 17 (4.9 g, 12.5 mmol) in AcOH (15 mL) wasadded sodium acetate (2.0 g, 2 eq.) and the mixture was stirred atreflux for 14 hours. After cooling to rt, the mixture was diluted withwater (150 mL) and extracted with diethyl ether (250 mL). The organiclayer was washed with a 1 N NaOH solution, dried over Na₂SO₄ and thesolvent evaporated. The title compound (3.24 g, 8.7 mmol) was obtainedas white crystals in a 72% yield; m.p. 82° C.

Intermediate 19:4-Hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid

To a solution of intermediate 18 (3.24 g, 8.7 mmol) in EtOH/H₂O (40mL/20 mL) was added NaOH (1.4 g, 4 eq.) and the mixture was stirred atreflux for 2 hours. After partial evaporation, water (100 mL) was addedand treated with a concentrated HCl solution to obtain pH=1. Theprecipitate was filtered off, washed with water and dried to give thetitle compound (2.38 g, 7.8 mmol) as white solid in a 90% yield; m.p.250-252° C.

Intermediate 20:4-Hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid[4-(4-{1-2-(tetrahydro-pyran-2-yloxy)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-2-yl}-piperidin-1-yl)-butyl]-amide

The same method was employed as in the preparation of intermediate 9 butstarting from intermediate 14 and intermediate 19 and gave the titlecompound as a beige powder in a 28% yield; m.p. 146-148° C.

Intermediate 21: 4′-Cyano-biphenyl-4-carboxylic acid[4-(4-{1-[2-(tetrahydro-pyran-2-yloxy)-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl}-piperidin-1-yl)-butyl]-amide

The same method was employed as in the preparation of intermediate 9 butstarting from intermediate 14 and 4′-cyano-biphenyl-4-carboxylic acidand gave the title compound as white oil in a 62% yield; LC/MS: M+HC₄₀H₄₉N₃O₄ 636.

Intermediate 22:1-[4-(1-Benzyloxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-yl]-ethanone

A solution of intermediate 2 (11 g, 40 mmol), K₂CO₃ (19.0 g, 1.5 eq.) inmethyl ethyl ketone (150 mL) was stirred at 80° C. for 10 minutes.Benzyl bromide (7.7 g, 1.1 eq.) was added and the mixture was stirred toreflux for 2.5 hours. After filtration, the filtrate was evaporated andthe residue washed with water, extracted with ether and evaporated off.The solid was washed with iPr₂O to give the title compound (9.5 g, 26.2mmol) as beige crystals in a 66% yield; m.p. 108-110° C.

Intermediate 23:4-(1-Benzyloxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidine

The same method was employed as in the preparation of intermediate 6 butstarting from intermediate 22 and gave the title compound which was useddirectly in the next step without purification; LC/MS: M+H C₂₂H₂₈NO 322.

Intermediate 24:2-{4-[4-(1-Benzyloxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-yl]-butyl}-isoindole-1,3-dione

The same method was employed as in the preparation of intermediate 7 butstarting from intermediate 23 and gave the title compound as an oil in aquantitative yield directly used in the next step without purification;LC/MS: M+H C₃₄H₃₉N₂O₃ 523.

Intermediate 25:4-[4-(1-Benzyloxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-yl]-butylamine

The same method was employed as in the preparation of intermediate 8 butstarting from intermediate 24 and gave the title compound as an oilwhich was directly used in the next step without purification; LC/MS:M+H C₂₆H₃₇N₂O 393.

Intermediate 26: 4′-Trifluoromethyl-biphenyl-4-carboxylic acid{4-[4-(1-benzyloxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-yl]-butyl}-amide

The same method was employed as in the preparation of intermediate 9 butstarting from intermediate 25 and4′-trifluoromethyl-biphenyl-4-carboxylic acid and gave the titlecompound as white crystals in 45% yield after recrystallisation inCH₃CN; m.p. 169-170° C.

Intermediate 27: 4′-Trifluoromethyl-biphenyl-4-carboxylic acid{4-[4-(1-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-yl]-butyl}-amide

To a mixture of intermediate 26 (4.0 g, 6.2 mmol) in EtOH (150 mL) wasadded Pd/C, 10% (0.6 g) and the reaction mixture was stirred under anatmospheric pressure of hydrogen at 60° C. for 2 hours. The mixture wasfiltered through a bed of celite. The filtrate was evaporated underreduced pressure to give the title compound (3 g, 5.4 mmol) as a whitecrystals after crystallisation from EtOH; m.p. 220-222° C.

Intermediate 28: 2-(4-Chloro-phenyl)-4-methyl-thiazole-5-carboxylic acid[4-(4-{1-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-2-yl}piperidin-1-yl)-butyl]-amide

To a solution of intermediate 14 (1.0 g, 2.33 mmol) in DMF (50 mL) wasadded the available 2-(4-chloro-phenyl)-4-methyl-thiazole-5-carboxylicacid (0.530 g, 0.9 eq.), HOBT (0.38 g, 1.2 eq.), EDCl (0.535 g, 1.2 eq.)and TEA (390 μL, 1.2 eq.) and the reaction mixture was stirred at rt for48 hours. After evaporation of the DMF, the product was dissolved inDCM. The organic layer was washed with a saturated NaHCO₃ solution,dried over Na₂SO₄, filtered and evaporated off. Purification by flashchromatography using DCM/MeOH 95/5 as eluent gave the title compound asa brown oil (0.815 g, 1.23 mmol) in a 53% yield; LC/MS: M+HC₃₇H₄₉ClN₃O₄S 666.

Intermediate 29: 2-Bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester

A solution of 2-methyl-1-nitrosooxy-propane (28.2 mL, 2.1 eq.) in CH₃CN(700 mL) was cooled to 0° C. and bromo-trimethyl-silane (32 mL, 2.1 eq.)was added dropwise over 20 min. A solution of the available2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (18.6 g, 0.1mol) in a mixture CH₃CN/EtOAc: 75/25 heated to 55° C. was added dropwiseover 45 min. During the addition the reaction was maintained at 0° C.and then allowed to warm to rt and stirred for 2 hours. Afterevaporation, the product was extracted with AcOEt, washed with water,dried over Na₂SO₄, filtered and evaporated. The title compound wasobtained as a yellow solid (21.74 g, 86.96 mmol) in a 87% yield; GC/MS:M⁺ C₇H₈BrNO₂S 250.

Intermediate 30: 2-(4-Cyano-phenyl)-4-methyl-thiazole-5-carboxylic acidethyl ester

To a solution of intermediate 29 (10.0 g, 40 mmol) in DMF (200 mL) wasadded Pd(PPh₃)₄ (2.76 g, 0.06 eq.), a 2M Na₂CO₃ solution (50 mL, 2.5eq.) and 4-cyanophenyboronic acid (11.68 g, 2.0 eq.) and the mixture wasstirred at 100° C. for 2 days. After evaporation of DMF, water was addedand the product was extracted with DCM and the organic layer wasfiltered through a bed of celite. The filtrate was dried over Na₂SO₄ andevaporated. The title compound was obtained as a white solid (10.1 g, 37mmol) in a 92.8% yield after purification by flash chromatography usingDCM/cyclohexane 80/20 and 90/10 as eluent; GC/MS: M+ C₁₄H₁₂N₂O₂S 272.

Intermediate 31: 2-(4-Cyano-phenyl)₄-methyl-thiazole-5-carboxylic acid

A suspension of intermediate 30 (4.0 g, 14.7 mmol) in EtOH (150 mL) wastreated with LiOH.H₂O (1.23 g, 2.0 eq.) and the mixture was stirred atrt for 2 days. After evaporation, the residue was acidified with a 1NHCl solution. The resulting precipitate was filtered and dried. Thetitle compound was obtained as a white solid (4.0 g, 16.39 mmol) in aquantitative yield; m.p. 265-270° C.

Intermediate 32: 2-(4-Cyano-phenyl)-4-methyl-thiazole-5-carboxylic acid[4-(4-{1-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-2-yl}-piperidin-1-yl)-butyl]-amide

The same method was employed as in the preparation of intermediate 28but starting from intermediate 14 and intermediate 31 and gave the titlecompound as a brown foam in a 39.5% yield after purification by flashchromatography using DCM/MeOH 90/10 as eluent; LC/MS: M+H C₃₈H₄₉N₄O₄S657.

Intermediate 33: 2-(2,4-Dichloro-phenyl)-4-methyl-thiazole-5-carboxylicacid ethyl ester

A solution of 2,4-dichloro-benzamide (19.0 g, 0.1 mol), P₄S₁₀ (8.88 g,0.2 eq.) and NaHCO₃ (16.8 g, 2.0 eq.) in toluene (200 mL) was heatedunder reflux for 1 hour. After concentration, the residue was purifiedthrough a bed of silica using DCM/AcOEt 80/20 as eluent. The isolated2,4-dichloro-thiobenzamide (5.0 g, 24.26 mmol) was dissolved in EtOH and2-chloro-3-oxo-butyric acid ethyl ester (3.3 mL, 1 eq.) in EtOH wasadded. The reaction was heated under reflux for 2 days. On cooling tort, the reaction mixture was filtered to give the title compound as pinkcrystals (1.57 g, 4.96 mmol) in a 5% global yield; m.p. 100° C.

Intermediate 34: 2-(2,4-Dichloro-phenyl)-4-methyl-thiazole-5-carboxylicacid

A suspension of intermediate 33 (1.56 g, 4.95 mmol) in EtOH (100 mL) wastreated with a 1N NaOH solution (15 mL, 3.0 eq.) and the reactionmixture was refluxed for 2 hours. After evaporation, the residue wasacidified with a 1N HCl solution. The resulting precipitate was filteredwashed with water and dried. The title compound was obtained as a whitesolid (1.42 g, 4.95 mmol) in a quantitative yield; LC/MS: M+HC₁₁H₈Cl₂NO₂S 288.

Intermediate 35: 2-(2,4-Dichloro-phenyl)-4-methyl-thiazole-5-carboxylicacid[4-(4-{1-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-2-yl}-piperidin-1-yl)-butyl]-amide

The same method was employed as in the preparation of intermediate 28but starting from intermediate 14 and intermediate 34 and gave the titlecompound as a yellow oil in a 41% yield after purification by flashchromatography using DCM/MeOH 95/5 as eluent; LC/MS: M+H C₃₇H₄₈Cl₂N₃O₄S700.

Intermediate 36: 2′,4′-dichloro-biphenyl-4-carboxylic acid[4-(4-{1-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-2-yl}-piperidin-1-yl)-butyl]-amide

The same method was employed as in the preparation of intermediate 28but starting from intermediate 14 and the available2′,4′-dichloro-biphenyl-4-carboxylic acid and gave the title compound asbeige crystals in a 43% yield after purification by flash chromatographyusing DCM/MeOH 95/5 as eluent; ¹H NMR (CDCl3, 300 MHz)

8.56 (t, 1H), 7.93 (d, 2H), 7.7 (m, 1H), 7.5 (m, 4H), 6.96 (d, 1H), 6.8(d, 1H), 4.7 (m, 1H), 3.89-1.49 (m, 37H).

Intermediate 37: 4′-Chloro-biphenyl-4-carboxylic acid[4-(4-{1-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-2-yl}-piperidin-1-yl)-butyl]-amide

The same method was employed as in the preparation of intermediate 28but starting from intermediate 14 and the available4-chloro-biphenyl-4-carboxylic acid and gave the title compound as beigecrystals in a 36% yield after purification by flash chromatography usingDCM/MeOH 95/5 as eluent; LC/MS: M+H C₃₉H₅₀ClN₂O₄ 645.

Intermediate 38: 2-(4-Cyano-phenyl)-4-methyl-oxazole-5-carboxylic acid

A solution of the available2-(4-cyano-phenyl)-4-methyl-oxazole-5-carboxylic acid methyl ester (1.0g, 4.13 mmol) in THF (50 mL) was treated with a 1N NaOH solution (4 mL,0.95 eq.) and the reaction was stirred at rt for 3 days. The reactionwas neutralised with 1N HCl solution and the solvent was evaporated. Theresidue was washed with water. The precipitate was filtered, washed withwater and dried to give the title compound as a white solid (0.94 g,4.13 mmol) in a quantitative yield; LC/MS: M+H C₁₂H₉N₂O₃ 229.

Intermediate 39: 2-(4-Cyano-phenyl)-4-methyl-oxazole-5-carboxylic acid[4-(4-{1-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-2-yl}-piperidin-1-yl)-butyl]-amide

The same method was employed as in the preparation of intermediate 28but starting from intermediate 14 and intermediate 38 and gave the titlecompound as a dark yellow oil in a 40% yield after purification by flashchromatography using DCM/MeOH 93/7 and 85/15 as eluents; LC/MS: M+HC₃₈H₄₉N₄O₅ 641.

Intermediate 40: N-(4-Bromo-phenyl)-methanesulfonamide

To a solution of 4-bromo-phenylamine (8.60 g, 50 mmol) and TEA (10.35 g,2.05 eq.) in DCM (100 mL) cooled to −78° C. was slowly added a solutionof methanesulfonyl chloride (6.01 g, 1.05 eq.) in DCM. The mixture waswarmed to rt and the mixture stirred overnight. Water was added and themixture was decantated. The aqueous layer was extracted with DCM and theorganic layer was dried over Na₂SO₄, filtered and evaporated off. Thetitle compound was obtained as a white solid (6.75 g, 27 mmol) in a 54%yield after purification by flash chromatography using DCM as eluent;m.p. 140-142° C.

Intermediate 41: 4′-Methanesulfonylamino-biphenyl-4-carboxylic acidmethyl ester

The same method was employed as in the preparation of intermediate 30but starting from intermediate 40 and the available4-methoxycarbonylphenylboronic acid and gave the title compound as apale grey solid in a 33.2% yield after recrystallisation from CH₃CN;m.p. 201-203° C.

Intermediate 42: 4-Methanesulfonylamino-biphenyl-4-carboxylic acid

The same method was employed as in the preparation of intermediate 34but starting from intermediate 41 and gave the title compound as a whitesolid in a quantitative yield. This intermediate was directly used inthe next step; LC/MS: M−H C₁₄H₁₂NO₄S 290

Intermediate 43: 4′-Methanesulfonylamino-biphenyl-4-carboxylic acid[4-(4-{1-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-2-yl}-piperidin-1-yl)-butyl]-amide

The same method was employed as in the preparation of intermediate 28but starting from intermediate 14 and intermediate 42 and gave the titlecompound as a yellow oil in a 26% yield after purification by flashchromatography using DCM/MeOH 85/15 as eluent. LC/MS: M+H C₄₀H₅₄N₃O₆S704.

EXAMPLES Example 1 4′-Trifluoromethyl-biphenyl-4-carboxylic acid(5-{4-[4-ethyl-2-(2-hydroxy-ethoxy)-phenyl]-piperidin-1-yl}-butyl)-amidehydrochloride

To a solution of intermediate 9 (0.28 g, 0.43 mmol) in MeOH/DCM 50/50(20 mL) was added 1N HCl (0.9 ml, 2 eq.) and the resulting mixturestirred at rt for 24 hours. The solvent was evaporated and the residuetreated with DCM/iPr₂O to give the title compound (0.080 g, 0.13 mmol)as white crystals in 31% yield; ¹H NMR (CDCl₃, 300 MHz)

8.25 (d, 2H), 7.8 (d, 6H), 7.15 (d, 1H), 6.8 (m, 2H), 4.2 (m, 4H), 3.8(m, 4H), 3.2 (m, 2H), 3-1.8 (m, 15H), 1.3 (t, 3H); LC/Tof: ES⁺ 569.29467.8 ppm.

Example 2 4′-Cyano-biphenyl-4-carboxylic acid(5-{4-[4-ethyl-2-(2-hydroxy-ethoxy)-phenyl]-piperidin-1-yl}-butyl)-amidehydrochloride

The same method was employed as in the preparation of example 1 butstarting from intermediate 10 and gave the title compound as whitecrystals in a 8% yield after recrystallisation in iPr₂O; LC/Tof: ES⁺526.3093 4.6 ppm; ¹H NMR (CDCl₃, 300 MHz)

8.1 (d, 2H), 7.7 (d, 6H), 6.95 (d, 1H), 6.7 (m, 2H), 4.2 (m, 4H), 4.0(m, 4H), 3.4 (m, 2H), 3.1-1.6 (m, 15H), 1.2 (t, 3H).

Example 34-Hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide

The same method was employed as in the preparation of example 1 butstarting from intermediate 20 and gave the title compound as beigecrystals in a 39% yield after recrystallisation in CH₃CN; m.p. 157-159°C.; LC/MS: M+H C₃₃H₄₁F₃N₃O₄S 632.

Example 4 4′-Trifluoromethyl-biphenyl-4-carboxylic acid(4-{4-[1-(2-ethoxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide

To a solution of TMAD (2.0 eq.) in dry THF under argon was addedtributylphosphine (2.2 eq.) and the mixture was stirred at rt for 10minutes. Intermediate 27 (1.0 eq) and 2-ethoxy-ethanol (1.2 eq.) wereadded and the mixture was stirred at rt for 48 hours. Water was addedand the reaction mixture evaporated. The residue was taken up into waterand the mixture filtered. After recrystallisation in CH₃CN, the titlecompound was obtained as white crystals in a 81% yield; m.p. 190° C.;LC/Tof: ES⁺ 623.3485 3.8 ppm.

Example 5 4′-Cyano-biphenyl-4-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amidehydrochloride

The same method was employed as in the preparation of example 1 butstarting from intermediate 21 and gave the title compound as whitecrystals in a 77% yield after recrystallisation in iPrO₂; m.p. 174° C.;LC/tof: ES+552.3176 9 ppm.

Example 6 2-(4-Chloro-phenyl)-4-methyl-thiazole-5-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide

A solution of intermediate 28 (0.815 g, 1.23 mmol) in MeOH (80 mL) wastreated with toluene-4-sulfonic acid (small quantity) and stirred atreflux for 70 hours. After evaporation, the product was dissolved withDCM and washed with a 1N NaOH solution. The organic layer was dried overNa₂SO₄, filtered and evaporated. The title compound was obtained as awhite solid (0.62 g, 1.06 mmol) in a 87% yield; m.p. 198° C.; LC/Tof:ES+ Calculated, 582.2557; Found, 582.2567 1.8 ppm.

Example 7 2-(4-Cyano-phenyl)-4-methyl-thiazole-5-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide,hydrochloride

A solution of intermediate 32 (0.6 g, 0.92 mmol) in DCM/MeOH (10 mL/10mL) was treated with 1N HCl and the reaction mixture was stirred at rtfor 24 hours. After concentration to dryness, acetone was added. Theresulting precipitate (hydrochloride form) was filtered and trituratedwith IprO₂. The title compound was obtained as a beige solid (0.51 g,0.84 mmol) in a 91.6% yield; m.p. 188° C.; LC/MS: M+H C₃₃H₄₁N₄O₃S 573.

Example 8 2-(2,4-dichloro-phenyl)-4-methyl-thiazole-5-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide

The same method was employed as in the preparation of example 6 butstarting from intermediate 35 and gave the title compound as a whitesolid in a 44% yield after recristallisation from IprO₂; m.p. 122-124°C.; LC/Tof: ES+ calculated, 616.2167; found, 616.2160-1.1 ppm.

Example 9 2′,4′-Chloro-biphenyl-4-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide

The same method was employed as in the preparation of example 6 butstarting from intermediate 36 and gave the title compound as a whitesolid in a 72% yield after recristallisation from CH₃CN; m.p. 145° C.;LC/Tof: ES+ Calculated 595.2494; Found, 595.2516 3.7 ppm.

Example 10 4′-Chloro-biphenyl-4-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide

The same method was employed as in the preparation of example 6 butstarting from intermediate 37 and gave the title compound as a whitesolid in a 73% yield after recrystallisation from CH₃CN; m.p. 162° C.;LC/Tof: ES+ Calculated 561.2884; Found 561.2886 0.3 ppm.

Example 11 2-(4-Cyanophenyl)-4-methyl-oxazole-5-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide

The same method was employed as in the preparation of example 6 butstarting from intermediate 39 and gave the title compound as a yellowsolid in a 50% yield after cristallisation from IprO₂; m.p. 109-111° C.;LC/Tof: ES+ Calculated, 557.3127; Found, 557.3069-10.4 ppm.

Example 12 4′-Methanesulfonylamino-biphenyl-4-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide

The same method was employed as in the preparation of example 6 butstarting from intermediate 43 and gave the title compound as a yellowsolid in a 41% yield purification by flash chromatography using DCM/MeOH85/15 as eluents; m.p. 216° C.; LC/MS: M+H C₃₅H₄₆N₃O₅S 620.

Biological Assays

The Examples were tested in vivo and/or in vitro according to thefollowing assay methods.

In Vitro Assay

HepG₂ cells, stably transfected with a construct comprising the LDL-rpromoter and the luciferase reporter gene, were seeded at 50.000cells/well in 96 well plates. After 1 day, cells were incubated withcompounds for 24 hours in RPMI medium containing 2% oflipoprotein-deficient serum. Compounds were tested from 10⁻⁸M to 10⁻⁹M.Cell lysates were prepared and the luciferase activity was measured bythe luciferase assay system (Promega). Induction of luciferase activitywas calculated taking untreated cells as control. The ED₅₀ of eachcompounds was determined compared to the ED₅₀ of an internal standard.

In Vivo Assay

Compounds were prepared for oral administration by milling with 0.5%hydroxypropylmethylcellulose and 5% Tween 80. Hamsters were fed for 2weeks with a diet containing 0.2% of cholesterol and 10% of coconut oil.Then compounds were administered once a day for 3 days, from 20 to 0.2mg/kg. Plasma lipid levels including total cholesterol, VLD/LDLcholesterol, VLD/LDL triglycerides and HDL-cholesterol were determinedafter ultracentrifugation (density 1.063 g/ml to separate VLD/LDLfraction and HDL fraction) using the Biomerieux enzymatic kit.Reductions in VLD/LDL cholesterol and TG plasmatic levels werecalculated taking solvent treated animals as control and ED₅₀ of eachcompound was determined.

The compounds of the invention are potent and specific inducers of LDL-rexpression.

Using the above in vitro assay all Examples of the invention inducedluciferase activity having EC₅₀ values in the range 1 nM to 64 nM.

2-(2,4-dichloro-phenyl)-4-methyl-thiazole-5-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}butyl)-amide(Example 8) had an EC₅₀ value of 13 nM.

4′-Methanesulfonylamino-biphenyl-4-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide(Example 12) had an EC₅₀ value of 5 nM.

1. A compound of formula (I)

wherein Ar₁ is: (i) phenyl, naphthyl or phenyl fused by aC₃₋₈cycloalkyl; or (ii) heterocyclyl selected from the group consistingof: monocyclic radicals and fused polycyclic radicals, wherein saidradicals contain a total of from 5-14 ring atoms, wherein said radicalscontain a total of from 1-4 ring heteroatoms independently selected fromoxygen, nitrogen and sulfur, and wherein individual rings of saidradicals may be independently saturated, partially unsaturated oraromatic, provided that at least one ring is aromatic; where Ar₁ isindependently substituted by at least one R¹ group and is independentlysubstituted by 0-3 R³ groups; Ar₂ is a phenyl group, a 5-6 memberedheteroaromatic group or a bicyclic heteroaromatic group, each of whichare optionally substituted by 1-4 groups independently selected from thelist: C₁₋₄alkyl, halogen, hydroxy, C₁₋₄alkoxy, C₁₋₆acyl, C₁₋₆acyloxy,amino, C₁₋₄alkylamino, di-C₁₋₄alkylamino, —(CH₂)_(n)OH,—(CH₂)_(n)NR_(x)R_(y), O(CH₂)_(n)O(CH₂)_(m)OR²,—O(CH₂)_(n)C(O)NR_(x)R_(y), —O(CH₂)_(n)CN, C₂-alkenyl,—O(CH₂)_(n)CO₂R²—OSO₂(CH₂)_(p)CH₃, —OSO₂NR_(x)R_(y) and—CO₂(CH₂)_(p)CH₃; Ar₃ is: (i) phenyl, naphthyl or phenyl fused by aC₃₋₈cycloalkyl; or (ii) heterocyclyl selected from the group consistingof monocyclic radicals and fused polycyclic radicals, wherein saidradicals contain a total of from 5-14 ring atoms, wherein said radicalscontain a total of from 1-4 ring heteroatoms independently selected fromoxygen, nitrogen and sulfur, and wherein individual rings of saidradicals may be independently saturated, partially unsaturated, oraromatic, providing that at least one ring is aromatic; wherein Ar₃ isoptionally substituted by 1-4 groups independently selected from thegroup consisting of: hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl,C₂₋₄alkenyloxy, C₁₋₄perfluoroalkoxy, C₁₋₄alkylsulfonylamino (such as—NHSO₂CH₃, —NHSO₂CH(CH₃)₂), fluoroC₁₋₄alkylsulfonylamino (such as—NHSO₂CH₂CF₃), C₁₋₄alkylcarbonylamino, fluoroC₁₋₄alkylcarbonylamino,halogen (such as chlorine), nitrile, nitro, C₁₋₄perfluoroalkyl,C₁₋₄alkylcarbonyl, fluoroC₁₋₄alkylcarbonyl, C₁₋₄alkoxycarbonyl,aminocarbonyl, C₁₋₄alkylaminocarbonyl, di-C₁₋₄alkylaminocarbonyl,C₁₋₄alkylsulfonyl, C₁₋₄alkylaminosulfonyl, di-C₁₋₄alkylaminosulfonyl,C₁₋₄alkylsulfonyl and C₁₋₄alkylsulfoxy; E is —C₁₋₁₆alkylene-; X is—CONR²— or —NR²CO—; wherein R¹ is O(CH₂)_(n)OR²; R² is C₁₋₄alkyl orhydrogen; R³ is halogen, C₁₋₄alkoxy or C₁₋₄alkyl; R_(x) and R_(y) areindependently C₁₋₄alkyl or hydrogen; n and m are independently 1-4; andp is 0-4; or a physiologically acceptable prodrug, salt or solvatethereof.
 2. A compound according to claim 1 wherein Ar₁ is phenyl,naphthyl, 1,2,3,4-tetrahydronaphthyl, indolyl, benzofuranyl,benzothiophenyl or indazolyl.
 3. A compound according to claim 1 whereinE is n-butylene.
 4. A compound according to claim 1 wherein X is—NR²CO—.
 5. A compound according to claim 1 wherein Ar₂ is phenyl or a5-6-membered heteroaromatic group.
 6. A compound according to claim 5wherein Ar₂ is optionally substituted by C₁₋₄alkyl, halogen, hydroxy,hydroxyC₁₋₄alkyl or C₁₋₄alkoxy.
 7. A compound according to claim 1wherein Ar₃ is phenyl, pyridyl or thienyl.
 8. A compound according toclaim 7 wherein Ar₃ is substituted by halogen, C₁₋₄perfluoroalkyl,nitrile, C₁₋₄acyl, C₁₋₄alkylsulfonyl, or C₁₋₄alkylsulfonylamino.
 9. Acompound according to claim 1 wherein R¹ is —OCH₂CH₂OR².
 10. A compoundaccording to claim 1 wherein Ar₁ is phenyl, naphthyl,1,2,3,4-tetrahydronaphthyl, indolyl, benzofuranyl, benzothiophenyl orindazolyl; where Ar₁ is independently substituted by at least one R¹group and is independently substituted by 0-3 R³ groups; Ar₂ is phenyl,pyridyl, thiazolyl, oxazolyl or imidazolyl, each of which are optionallysubstituted by 1-4 groups independently selected from the group;C₁₋₄alkyl, halogen, hydroxy, hydroxyC₁₋₄alkyl and C₁₋₄alkoxy; Ar₃ isphenyl, pyridyl or thienyl, wherein Ar₃ is optionally substituted by 1-4groups independently selected from the group consisting of: halogen,C₁₋₄perfluoroalkyl, nitrile, C₁₋₄acyl, C₁₋₄alkylsulfonyl, andC₁₋₄alkylsulfonylamino; E is n-butylene; X is —NR²CO—; wherein R¹ is—OCH₂CH₂OR²; R² is C₁₋₄alkyl or hydrogen; R³ is halogen, C₁₋₄alkoxy orC₁₋₄alkyl; and n is 1-4.
 11. A compound according to claim 1 selectedfrom the group consisting of:4-Hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide;4′-Cyano-biphenyl-4-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amidehydrochloride; 2-(4-Cyano-phenyl)-4-methyl-thiazole-5-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide,hydrochloride; 2-(2,4-dichloro-phenyl)-4-methyl-thiazole-5-carboxylicacid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide;2′,4′-Chloro-biphenyl-4-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide;4′-Chloro-biphenyl-4-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide;and 4′-Methanesulfonylamino-biphenyl-4-carboxylic acid(4-{4-[1-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-1-yl}-butyl)-amide.12. A pharmaceutical composition comprising a compound as defined inclaim 1 and a pharmaceutically acceptable carrier or diluent. 13.(canceled)
 14. (canceled)
 15. A method for the treatment of a conditionresulting from elevated circulating levels of LDL-cholesterol in amammal in need thereof, said method comprising administering atherapeutically effective amount of a compound according to claim 1.